Role of Chitinase-3-like 3 protein in endogenous oligodendrogenesis and remyelination during experimental multiple sclerosis

在脱髓鞘疾病中，如多发性硬化症（MS）及其小鼠模型实验性自身免疫性脑脊髓炎（EAE），少突生长和再髓鞘生成失败导致慢性脱髓鞘和轴突变性，造成毁灭性的残疾。因此，了解驱动少突胶质形成的分子和细胞机制对于制定髓鞘再生的治疗策略至关重要。尽管髓鞘再生一直被认为是由实质少突胶质前体细胞（pOPSc）驱动的，但我们和其他人已经表明，如果局部微环境允许，来自脑室下区的成体神经干细胞（NSCs）在脱髓鞘反应中被激活，并显著促进髓鞘修复。我们已经证明几丁质酶-3-like-3 (Chi3l3)，也被称为Ym1，形成了这个允许的局部微环境的一部分，并通过激活神经干细胞和OPCs诱导髓鞘少突胶质细胞的产生。此外，我们已经表明，沉默内源性Chi3l3表达会加重EAE的疾病严重程度，减少少突胶质形成和髓鞘再生。我们的研究结果表明，Chi3l3是迄今为止未知的少突发生命运选择和髓鞘再生的内在诱导剂。这就提出了一个问题，即治疗应用Chi3l3是否可以用于调节不同疾病阶段的少突胶质形成、髓鞘再生和临床症状，以及与pOPC驱动的修复相比，神经干细胞驱动的修复在多大程度上有助于临床改变。为了研究这些问题，我的目标是在复发-缓解型EAE的不同阶段应用chi313治疗，随后通过免疫组织化学/共聚焦分析和流式细胞术结合分析内源性修复。使用野生型SJL小鼠将允许详细表征NSC和OPC驱动的少突胶质细胞形成/再髓鞘形成及其与临床疾病调节的相关性。额外使用nesting - hsvtk SJL小鼠（一种用于体内NSCs条件耗尽的工具），将允许在非操纵和治疗条件下，NSCs驱动的功能性再髓鞘形成与临床症状变化之间的因果联系。通过这种方式，我将描述Chi3l3的治疗潜力和潜在的细胞修复机制，最终目标是为多发性硬化症和其他脱髓鞘疾病开发有效的脱髓鞘治疗方法。

In demyelinating diseases, such as multiple sclerosis (MS) and its mouse model experimental autoimmune encephalomyelitis (EAE), failure of oligodendrogenesis and remyelination result in chronic demyelination and axon degeneration, causing devastating disabilities. Thus, understanding the molecular and cellular mechanisms that drive oligodendrogenesis is crucial for developing therapeutic strategies for remyelination.Although remyelination has long been considered to be driven by parenchymal oligodendrocyte precursor cells (pOPSc), we and others have shown that adult neural stem cells (NSCs) from the subventricular zone get activated in response to demyelination and significantly contribute to myelin repair, if local microenvironments allow. We have demonstrated that Chitinase-3-like-3 (Chi3l3), also known as Ym1, forms part of this permissive local microenvironment and induces the generation of myelinating oligodendrocytes by activating both neural stem cells and OPCs. Additionally, we have shown that silencing endogenous Chi3l3 expression aggravates disease severity and reduced oligodendrogenesis and remyelination in EAE. Our results show that Chi3l3 constitutes an hitherto unknown intrinsic inductor for oligodendrogenic fate choice and remyelination. This raises the question as to whether therapeutic application of Chi3l3 can be used to modulate oligodendrogenesis, remyelination and clinical symptoms in different disease phases and to which extent neural stem cell-driven repair – in contrast to pOPC driven repair- contributes to clinical changes.To investigate these questions, I aim here to apply Chi3l3-treatment in different phases of the relapsing-remitting EAE, and subsequently analyze endogenous repair by a combination of immunohistochemical/ confocal analysis and flow cytometry. The use of wild type SJL mice will allow the detailed characterization of NSC- and OPC- driven oligodendrogenesis/remyelination and its correlation to clinical disease modulation. The additional use of Nestin-HSVTK SJL mice, a tool for conditional depletion of NSCs in vivo, will allow the causal link between NSC-driven functional remyelination and changes in clinical symptoms, both under non-manipulated and therapeutic conditions. This way I will delineate the therapeutic potential of Chi3l3 and the underlying cellular mechanism of repair with the ultimate goal to develop effective remyelinating therapies for MS and other demyelinating disorders.